Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the plasma. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD). Elevated levels of blood cholesterol, especially low-density lipoprotein
cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for CHD. The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear; however, it is known that some lipoprotein subfractions are more associated with hardening of the arteries than others. Therefore examination of specific lipoprotein subclasses and their modulation by genetics, diet and therapeutic agents could contribute to an improved understanding of the dynamic interaction between ethnicity, genetics, dietary factors, lipid metabolism and CHD. Our goal was to examine whether there were additional genetic differences between racial/ethnic groups on lipoprotein profile. First, genotypes were assessed in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Significant associations with lipoprotein sizes were replicated in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA).Variants that replicated across both Caucasian populations were subsequently tested for association in the African-American, Chinese, and Hispanic populations of MESA. Variants in the APOB gene region were significantly associated with mean very-low-density lipoprotein (VLDL) diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with average HDL diameter in both Caucasians populations only. Our findings suggest that the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of insulin resistance and CVD that are sensitive to race/ethnicity.

Technical Abstract:
Specific constellations of lipoprotein particle features, reflected as differences in mean lipoprotein particle diameters, are associated with risk of insulin resistance (IR) and cardiovascular disease (CVD). The associations of lipid profiles with disease risk differ by race/ethnicity, the reason for this is not clear. We aimed to examine whether there were additional genetic differences between racial/ethnic groups on lipoprotein profile. Genotypes were assessed using the Affymetrix 6.0 array in 817 related Caucasian participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). Association analysis was conducted on fasting mean particle diameters using linear models, adjusted for age, sex and study center as fixed effects, and pedigree as a random effect. Replication of associations reaching P < 1.97 × 10(-05) (the level at which we achieved at least 80% power to replicate SNP-phenotype associations) was conducted in the Caucasian population of the Multi-Ethnic Study of Atherosclerosis (MESA; N = 2,430). Variants which replicated across both Caucasian populations were subsequently tested for association in the African-American (N = 1,594), Chinese (N = 758), and Hispanic (N = 1,422) populations of MESA. Variants in the APOB gene region were significantly associated with mean VLDL diameter in GOLDN, and in the Caucasian and Hispanic populations of MESA, while variation in the hepatic lipase (LIPC) gene was associated with mean HDL diameter in both Caucasians populations only. Our findings suggest that the genetic underpinnings of mean lipoprotein diameter differ by race/ethnicity. As lipoprotein diameters are modifiable, this may lead new strategies to modify lipoprotein profiles during the reduction of IR that are sensitive to race/ethnicity.